Early detection of metastatic disease in US Veterans following surgery for early stage lung cancer Surgery remains the most effective treatment for early stage non-small-cell lung cancer (NSCLC). This therapeutic mainstay, however, is plagued by the development of post-surgical recurrence which most often presents as metastatic disease. No significant improvements have been developed in the past 15 years and, following surgery, the overall 5-year survival rate remains below 50%. New effective strategies that overcome the major obstacles related to metastases will improve lung cancer cure rates and make a major impact in VA patient care. Detection of NSCLC at an early stage results in favorable survival outcomes. In Aim 1 we will identify molecular and cellular profiles that predict aggressive disease resulting in lung cancer metastasis following surgery by conducting the following subaims: A) Identify and characterize somatic mutations that differ between aggressive versus indolent lung cancers using whole exome sequencing, B) Develop tumor gene expression signatures associated with important driver mutations and determine whether gene expression signatures group tumors with biologically related mutations and thereby serve as markers for distinguishing between aggressive and indolent lung cancers and C) Characterize the immune cell phenotypes found within the tumor microenvironment that distinguish aggressive and indolent lung cancers. In Aim 2 we will develop a novel highly sensitive approach for Minimum Residue Disease (MRD) and cancer recurrence detection by conducting the follow subaims: A) Identify truncal mutations from pre-surgery plasma circulating tumor DNA (cfDNA) samples, B) Detect MRD/recurrence using post-surgery plasma cfDNA samples and C) Assess the statistical significance of the MRD predictive score in the determination of recurrence. In this VA Merit Review Supplement proposal we will conduct a pilot study that begins to develop the requisite platforms that facilitate our understanding, prediction, and detection of NSCLC metastases in US Veterans.